Table 1.

Summary of Studies Investigating Receptor Interacting Protein Kinases in Cardiovascular Disease.

Disease	Model/Subjects	Inhibitor	Pertinent Findings	Ref.
Atherosclerosis	Human plaques, Apoe−/− mice, oxLDL BMDM treatment	Nec-1	RIPK3 and MLKL expression & activation increased in human plaques, Nec-1 reduces plaque size/necrotic core in mice, reduced ox-LDL induced necroptosis in BMDM	[12]
Atherosclerosis	Human plaques, in vitro serum starvation foam cell model	None	RIPK1/3 expression increased in plaques, serum starvation increases RIPK1/RIPK3 expression, MLKL oligomerization	[19]
Atherosclerosis	ox-LDL HUVEC treatment	Nec-1	Ox-LDL increases RIPK1 expression & inflammation, nec-1 ameliorates this effect	[21]
Atherosclerosis	Ripk3−/−; Ldlr−/− mice, Apoe−/− mice	None	Ripk3−/Ldlr−/− mice−mice have significantly smaller advanced plaques	[22]
Atherosclerosis	Apoe−/− mice	Anti-sense MLKL oligonucleotides	MLKL knockdown decreased necrotic core size but not plaque size, decreased lipid levels	[26]
MI	Rat LAD ligation	Nec-1	RIPK1/RIPK3 increased in cardiac tissue after MI, Nec-1 decreased infarct size	[30]
MI	Mouse LAD ligation, Ripk3−/− mice	None	RIPK3 increased in cardiac tissue after MI, EF preserved in Ripk3−/− mice after LAD ligation	[31]
MI	Mouse and rat-derived cardiomyocytes, mouse LAD ligation	Nec-1	Nec-1 reduced peroxide induced cell death, murine infarct size	[33]
MI	Mouse LAD ligation	Nec-1	Nec-1 reduced infarct size, necrotic cell death, prevented adverse remodeling at 28 days	[34]
MI	Ripk3−/− mice, Mouse LAD ligation	None	Reduced infarct size in Ripk3−/− mice	[35]
MI	Human STEMI patients	None	In patients with normal troponin on presentation, serum RIPK3 predicts impaired LV function	[41]
MI	Humans with CAD, angina, unstable angina	None	Plasma RIPK3 correlates with CAD severity	[42]
Stroke	Mouse MCAO model	Nec-1	Intracerebroventricular Nec-1 reduced infarct volume	[32]
Stroke	Oxygen-deprived glucose (ODG) in vitro model, MCAO mouse model	GSK’872	ODG and MCAO upregulate RIPK1, RIPK3, MLKL, GSK’872 reduces infarct volume	[46]
Stroke	Rat MCAO model	Nec-1	Ischemia activates RIPK1/3/MLKL signaling. Nec-1 reduces infarct volume	[47]
Stroke	Mouse MCAO model, Ripk3−/− mice, Ripk1D138N/D138N mice	None	Inactivation of RIPK1 and absence of RIPK3 can ultimately decrease stroke volume, improve behavioral scores	[48]
Stroke	Mouse MCAO model, ODG in vitro model, Ripk3−/− and Mlkl−/− mice	None	RIPK3 or MLKL deficiency decreases stroke size, neurologic deficits, polarizes macrophages to M2 phenotype	[49]
Stroke	Mouse MCAO model, ODG in vitro model	Nec-1	Nec-1 protects cells from ODG related death, Nec-1 reduced infarct volume	[50]
Stroke	Mouse MCAO model	NSA	Decreased infarct size, neurologic deficits, MLKL levels; increased MLKL degradation after NSA treatment	[51]
Stroke	Photothrombosis induced ischemic injury in mouse	Dabrafenib	Dabrafenib reduced infarct size, inflammation	[52]
AAA	Murine elastase perfusion model, Ripk3−/− mice	None	RIPK1/RIPK3 are locally upregulated in AAA, Ripk3−/− mice are protected from AAA	[58]
AAA	Murine elastase perfusion model	Nec-1s	Nec-1s slows aneurysm growth, decreases inflammation, preserves vessel architecture	[64]
AAA	Murine CaCl2 model, murine AngII Apoe−/− model	GSK’074	GSK’074 can prevent aneurysm growth, preserve vessel architecture in both aneurysm models	[65]
AAA	Murine CaCl2 model	GSK’074	GSK’074 slows aneurysm growth, preserves vessel architecture	[66]
AAA	Murine AngII and CaCl2 model, cell culture	None	STING deficiency decreases necroptosis and protects mice from AAA	[62]
Arterial thrombosis	Murine FeCl3 injury model, tail bleeding, platelet activity assays, Ripk3−/− mice	None	Ripk3−/− mice have prolonged tail bleeding, FeCl3 arteriole time to occlusion, abnormal dense granule secretion	[76]
Venous Thrombosis	IVC ligation model, Mlkl−/− mice	Nec-1s, NSA	Nec-1s treatment and MLKL deficiency decrease thrombus size, decrease NETosis. Nec-1s and necrosulfonamide decrease platelet-neutrophil aggregation	[86]

AAA, abdominal aortic aneurysm; AngII, angiotensin II; BMDM, bone marrow-derived macrophage; EF, ejection fraction; IVC, inferior vena cava; LAD, left anterior descending artery; LV, left ventricle; MCAO, middle cerebral artery occlusion; MI, myocardial infarction; MLKL, mixed-lineage kinase domain like protein; Nec-1, Necrostatin-1; Nec-1s, Necrostatin-1s; NSA, Necrosulfonamide; oxLDL, oxidized low density lipoprotein; RIPK, receptor interacting protein kinase; STEMI, ST-elevation myocardial infarction.